Ischemic heart disease typically results from an imbalance between the myocardial blood flow and the metabolic demand of the myocardium. Progressive atherosclerosis with increasing occlusion of coronary arteries leads to a reduction in coronary blood flow. “Atherosclerosis” is a type of arteriosclerosis in which cells including smooth muscle cells and macrophages, fatty substances, cholesterol, cellular waste product, calcium and fibrin build up in the inner lining of a body vessel. “Arteriosclerosis” refers to the thickening and hardening of arteries. Blood flow can be further decreased by additional events such as changes in circulation that lead to hypoperfusion, vasospasm or thrombosis.
Myocardial infarction (MI) is one form of heart disease that often results from the sudden lack of supply of oxygen and other nutrients. The lack of blood supply is a result of a closure of the coronary artery (or any other artery feeding the heart) which nourishes a particular part of the heart muscle. The cause of this event is generally attributed to arteriosclerosis in coronary vessels.
Formerly, it was believed that an MI was caused from a slow progression of closure from, for example, 95% then to 100%. However, an MI can also be a result of minor blockages where, for example, there is a rupture of the cholesterol plaque resulting in blood clotting within the artery. Thus, the flow of blood is blocked and downstream cellular damage occurs. This damage can cause irregular rhythms that can be fatal, even though the remaining muscle is strong enough to pump a sufficient amount of blood. As a result of this insult to the heart tissue, scar tissue tends to naturally form.
An important component in the progression to heart failure is remodeling of the heart due to mismatched mechanical forces between the infarcted region and the healthy tissue resulting in uneven stress and strain distribution in the left ventricle (LV). Once an MI occurs, remodeling of the heart begins. The principle components of the remodeling event include myocyte death, edema and inflammation, followed by fibroblast infiltration and collagen deposition, and finally scar formation. The principle component of the scar is collagen. Since mature myocytes of an adult are not regenerated, the infarct region experiences significant thinning. Myocyte loss is the major etiologic factor of wall thinning and chamber dilation that may ultimately lead to progression of cardiac myopathy. In other areas, remote regions experience hypertrophy (thickening) resulting in an overall enlargement of the left ventricle. This is the end result of the remodeling cascade. These changes in the heart result in changes in the patient's lifestyle and their ability to walk and to exercise. These changes also correlate with physiological changes that result in increase in blood pressure and worsening systolic and diastolic performance.
Currently, methods to alleviate LV remodeling, including application of cells, biomaterials (also known as “bioscaffoldings”), or cell-loaded bioscaffoldings to an injury site (e.g., compromised heart tissue), have been preliminarily explored. Implantation of autologous cells for damaged myocardium is under current clinical investigation. In other recent studies, implanting biomaterials to an infarct region has been shown to improve the ejection fraction in rats. See Christman, K. L., Biomaterials for the Treatment of Myocardial Infarction, J. American College of Cardiology, vol. 48, no. 5 (2006). Limitations of current methods include low cell retention at the injury site and reduced long-term viability of injected or endogenous cells.
Growth factors are naturally occurring proteins secreted by many different cell types for signaling to induce cell migration, differentiation, survival, or proliferation, in addition to other functions. Signaling occurs through binding of factors to cell surface specific receptors. Signals can be amplified within the cell to regulate specific gene expression. Growth factors typically act in a dose- and time-dependent fashion with small variations in concentrations resulting in a biological effect. When applied in post-MI therapies, growth factors have the potential to increase the survival of cells whether endogenous or exogenous. Current growth factor therapies for both acute MI and HF have focused on bolus or systemic injection of a single growth factor type. Such therapies, however, are subject to a large percentage of the growth factor being washed away by blood flow thus minimizing the potential benefit of the treatment agent that may otherwise be obtained. Moreover, application of a single growth factor may not be as beneficial as previously hypothesized in view of naturally occurring complex growth factor signaling pathways.